Functions for novel IL-15-responsive macrophages in the uterus during pregnancy

妊娠期间子宫内新型 IL-15 反应性巨噬细胞的功能

• 批准号: 10817297
• 负责人: Scott Michael Gordon
• 金额: $ 3.78万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10817297
• 关键词: Advisory Committees; Award; Biochemical; Cells; Cellular Immunology; Child; Child Support; Clinical; Complement; Data; Disease; Doctor of Philosophy; Ensure; Event; Exposure to; Faculty; Fetal Development; Fetal Growth; Fetal health; Fetus; Funding; Genetic Transcription; Goals; Growth; Homeostasis; Human; Human Resources; IL2RB gene; Immune; Immunity; Inflammatory; Institution; Interleukin-15; International; K-Series Research Career Programs; Knowledge; Laboratories; Life; Literature; Lymphocyte; Macrophage; Maternal Health; Mentors; Mothers; Mus; Natural Immunity; Natural Killer Cells; Neonatology; Pediatric Hospitals; Pennsylvania; Philadelphia; Physicians; Placenta; Placental Biology; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Productivity; Property; Public Health; Reproductive Immunology; Research; Research Personnel; Research Support; Resources; Rheumatology; Role; Scientist; Signal Transduction; United States National Institutes of Health; Universities; Uterus; Work; adverse pregnancy outcome; caregiving; cellular targeting; fetal; in vivo; inflammatory modulation; innovation; interest; maternal outcome; next generation sequencing; novel; professor

PROJECT SUMMARY The goal of my five-year Mentored Clinical Scientist Research Career Development Award is for me to develop into a productive, independent academic investigator in the field of reproductive immunology. I completed an MD and a PhD in the field of cellular immunology, and I now seek to apply my interest in dysregulated immunity to the public health threat of adverse fetal and maternal outcomes of pregnancy. I am now a physician-scientist in Neonatology and Assistant Professor on faculty at Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania (Penn). My primary mentor for this award, Dr. Edward M. Behrens, is a physician-scientist and Chief of the Division of Rheumatology with a longstanding track record of scientific innovation and providing exceptional mentoring to trainees at all levels. As an internationally-recognized expert in innate immunity and inflammatory disorders, Dr. Behrens’s work complements my own. We are thus poised for productivity. My scientific advisory committee includes scientists and physician-scientists with collective expertise in all aspects of the proposed work, from placental biology to next-generation sequencing. I am also extremely fortunate to have the unreserved support of CHOP and Penn, whose combined resources are unmatched. The goal of this one-year supplement is to provide funding for additional personnel who will promote my to return to full research productivity after facing a critical life event soon after opening my laboratory. Given the extent of my caregiving responsibilities for my two young children during this period, I have already received an extension of the tenure clock from my supportive institution. This supplemental research support from the NIH will be instrumental in timely completion of the original aims of my K08. Scientifically, the proposal focuses on roles for novel macrophages that I discovered under the guidance of Dr. Behrens, called CD122+Macs, in normal and threatened pregnancy. Enriched in the uterus in mice and humans, CD122+Macs express high levels of CD122, the hallmark of responsiveness to interleukin-15 (IL-15). These novel Macs signal and function when exposed to IL-15, surprising because killer lymphocytes like natural killer (NK) cells, not Macs, are the classical targets of IL-15. Disrupted homeostasis of IL-15 is associated with numerous adverse outcomes of pregnancy, including preeclampsia and abnormal feto-placental growth but through unknown mechanisms. Based on prior literature and my preliminary data, my central hypothesis is: IL- 15 exerts its influence over outcomes of pregnancy not only by maintaining NK cells but also by modulating the inflammatory properties of novel CD122+Macs. The aims of this proposal will establish: 1) Mechanisms by which CD122+Macs respond biochemically and transcriptionally to IL-15 and 2) IL-15-dependent requirements for CD122+Macs in pregnancy in vivo. This proposal will close major gaps in knowledge regarding the mechanism by which IL-15 acts on a novel cellular target to ensure maternal and fetal health during pregnancy.

项目摘要 我的五年指导临床科学家研究职业发展奖的目标是让我发展 成为生殖免疫学领域的一名富有成效的独立学术研究者。我完成了医学博士学位 和细胞免疫学领域的博士学位，我现在寻求将我对免疫失调的兴趣应用于 妊娠对胎儿和母亲的不良后果构成的公共卫生威胁。我现在是一名物理学家， 费城儿童医院（CHOP）和大学的新生儿学和助理教授 宾夕法尼亚州（Penn）我获得这个奖项的主要导师，爱德华·M·Behrens是一位物理学家兼科学家， 流变学系主任，长期致力于科学创新， 为各级学员提供出色的指导。作为国际公认的先天免疫专家， 炎症性疾病贝伦斯医生的研究与我的研究相辅相成因此，我们已作好生产力的准备。我 科学咨询委员会包括在各方面具有集体专长的科学家和医生-科学家 从胎盘生物学到下一代测序。我也非常幸运， 有CHOP和宾夕法尼亚大学的无保留的支持，他们的综合资源是无与伦比的。 这个为期一年的补充的目标是为促进我返回的额外人员提供资金 在我的实验室开放后不久，我就面临着一个关键的生活事件。考虑到 在此期间，我对我的两个年幼的孩子负有责任，我已经得到了延期。 从我的支持机构获得终身教职的时间。NIH的这项补充研究支持将 有助于及时完成我的K 08的原始目标。科学上，该提案侧重于以下方面的作用： 我在Behrens博士的指导下发现的新型巨噬细胞，称为CD 122 +Macs，在正常和 威胁怀孕。在小鼠和人类的子宫中富集，CD 122 +Macs表达高水平的CD 122， 对白细胞介素-15（IL-15）反应性的标志。这些新颖的Mac信号和功能时，暴露 IL-15，令人惊讶的是，因为像自然杀伤（NK）细胞，而不是Macs这样的杀伤淋巴细胞是IL-15的经典靶点。 IL-15。IL-15稳态的破坏与许多妊娠不良结局相关，包括 先兆子痫和异常胎儿-胎盘生长，但通过未知的机制。基于先前文献 根据我的初步数据，我的中心假设是：IL- 15对妊娠结局产生影响， 不仅通过维持NK细胞，还通过调节新型CD 122 +Macs的炎症特性。的 本提案的目标将建立：1）CD 122 + Mac的生物化学反应机制， 2）IL-15对体内妊娠中CD 122 +Macs的依赖性需求。这 这项提案将填补有关IL-15作用于新的细胞因子的机制的知识空白。 目标是确保怀孕期间产妇和胎儿健康。